Substance dependency is a prevalent disease both domestically and abroad, with substantial morbidity and mortality associated with the disease state. Typically detoxification and psychosocial therapy are the primary treatments, however, pharmaceutical treatment has gained acceptance as a feasible treatment alternative. One such treatment, naltrexone, a mu opioid receptor antagonist, is used in the treatment of opioid and alcohol dependence. Naltrexone's longer duration of action compared to naloxone (another pharmaceutical substance abuse treatment) has been considered to be due partly to its major human metabolite, 6-beta-naltrexol (i.e., morphinan-3,6,14-triol,17-(cyclopropylmethyl)-4,5-epoxy). The potency of 6-beta-naltrexol in vivo is time-dependent, and it has a longer duration of action than naloxone and naltrexone, consistent with a longer pharmacokinetic terminal half-life.
Beyond their use to treat substance dependency, opioid antagonists have also been shown to be useful in the treatment of pruritis associated with liver disease or opioid medications. However, despite a wide range of clinical applications, the primary disadvantages of treatment with an opioid antagonist such as naltrexone or naloxone, is the possibility of inducing withdrawal, due to the receptor blocking qualities of the therapeutic agents. Clinical trials have shown that treatment with 6-beta-naltrexol precipitated only minimal withdrawal at high doses in an acute dependence model and was approximately 77-and 30-fold less potent than naltrexone and naloxone, respectively, in precipitating withdrawal in a chronic dependence model. 6-Beta-naltrexol is available in both the base and hydrochloride salt forms of the medication. Drug delivery systems for 6-beta-naltrexol can include IV, oral, and trans-dermal methods, in which solubility is critical to all dosage forms. Despite its therapeutic uses, no polymorphs of 6-beta-naltrexol have been characterized.
Solids exist in either amorphous or crystalline forms. In the case of crystalline forms, molecules are positioned in three-dimensional lattice sites. When a compound recrystallizes from a solution or slurry, it may crystallize with different spatial lattice arrangements, and the different crystalline forms are sometimes referred to as “polymorphs.” The different crystalline forms of a given substance may differ from each other with respect to one or more chemical properties (e.g., dissolution rate, solubility), biological properties (e.g., bioavailability, pharmacokinetics), and/or physical properties (e.g., mechanical strength, compaction behavior, flow properties, particle size, shape, melting point, degree of hydration or salvation, caking tendency, compatibility with excipients). The variation in properties among different crystalline forms usually means that one crystalline form is desired or preferred over other forms.
Because 6-beta-naltrexol exhibits several advantageous therapeutic properties, such as a longer half-life, and decreased likelihood of inducing withdrawal, improved forms of the compound are desired, particularly with regard to enhanced solubility, bioavailability, ease of synthesis, ability to be readily formulated, and/or physical stability. Thus, there is a need for improved crystalline forms of 6-beta-naltrexol and methods for preparing the different forms.